The measurement of the levels of blood borne analytes, including glucose, urea, cholesterol, and/or hemoglobin in a patient is an often utilized clinical procedure. Typically a needle or some other device is used to deeply penetrate a patient's skin and draw a sample, such as blood, which is then analyzed by chemical techniques to determine the concentration of the analyte(s) of interest. The drawbacks of these procedures include the pain and apprehension experienced by the patient, the risk of infection to both the patient and any health care worker handling the sample or the sample-taking device, and the delay in feedback associated with sending the sample to a laboratory for analysis.
Noninvasive techniques have been developed in order to overcome the drawbacks of the invasive techniques. For example, as described in my U.S. Pat. No. 5,377,674, the disclosure of which is incorporated herein by reference, one such branch of noninvasive techniques involves the use of spectroscopy. Spectroscopy deals with the measurement and interpretation of light waves resulting from exposing a substance to a known light wave. The measurements can be based on the reflectance, transmission or emission of the light wave. When exposing a mixture of substances to a known light wave, each of the substances absorbs, to varying degrees, parts of the light wave. As a result of this absorption, a unique light wave is created. Thus, the unique resultant light wave can be measured and interpreted to determine the presence and concentration of substances that make-up the mixture. We have shown in prior work that spectral regions may be normalized prior to PLS analysis by dividing by the area of the absolute value of the derivative spectrum to yield analyte concentration information. (Kuenstner et al., "Rapid Measurement of Analytes in Whole Blood with NIR Transmittance," Leaping Ahead with Near Infrared Spectroscopy, edited by G. Batten et al., Proceedings of the 6th International Conference on Near Infrared Spectroscopy at Lorne, Australia in April 1994).
Development of noninvasive techniques utilizing spectroscopy for glucose monitoring would be particularly advantageous because of the large number of diabetics who would benefit from such a discovery. Currently, glucose testing requires taking a blood sample with the use of a steel lancet as often as 4 times a day. The sample is then analyzed using a glucose meter. The meter, however, requires the blood sample to be collected on a reagent strip. Reagent strips are not re-usable and are a significant expense for diabetics who need to frequently monitor their glucose level.
Infrared (IR) light has been used for glucose measurement in current noninvasive spectroscopic techniques. These techniques typically involve the use of an Attenuated Total Reflectance (ATR) accessory in combination with Partial Least Squares (PLS) and/or Partial Least Squares with Artificial Neural Networks (PLS-ANN) analysis to measure the resultant light wave and determine the concentration of glucose in the sample. The equipment and methods required to perform these techniques, however, are quite complicated.
A major disadvantage of these techniques is the requirement of ATR accessories. Generally, ATR accessories include a special crystal that precisely modifies the path length of the infrared light in relation to the sample. The ATR crystal directs the light to be reflected between the bottom of the sample and the crystal a number of times. This results in reflected wave measurements that change over time if a suspension like blood is used. Measurements on a suspension such as blood made with an ATR crystal change over time as a result of settling of constituents within the blood sample. For example, the concentration of red blood cells at the bottom surface of a sample of whole blood will increase over time as the red blood cells settle to the bottom of the sample. This phenomenon creates problems in the ATR measurement technique.
Also, special equipment arranged in a precise set-up is required to measure the resultant reflected light waves. The set up needs to be precise to guarantee a specific incident angle of the light. Additionally, the ATR crystal must often be thoroughly cleaned between samples in order to obtain accurate results. Thus, problems with crystal cleaning and instrument readjustment in such an exacting environment do not lend these methods to quick, easy and simple use by diabetics.
Efforts have been made to avoid some of the problems associated with the ATR accessories while maintaining at least a similar level of accuracy. For example, Budinova et al. took spectroscopic measurements on dried blood and serum samples using infrared transmission. G. Budinova, J. Salva and K. Volka, "Application of Molecular Spectroscopy in the Mid-Infrared Region for the Determination of Glucose and Cholesterol in Whole Blood and in Blood Serum," Applied Spectroscopy, Vol. 51(5), p. 631, 1997. Measuring the transmittance of infrared waves is less complex than the ATR measurements, but there are some drawbacks. For example, dried samples were required because of the difficulty in obtaining accurate results with liquid blood or serum. Budinova et al. found that "transmittance measurements of liquid blood or serum are impossible in the mid-IR because of the presence of water in the matrix." Id. They disclose a method requiring careful pipetting of a fixed volume of sample onto a polyethylene carrier, and then drying the sample prior to spectroscopic analysis. Additionally, they normalized the resultant spectrum by multiplying by the ratio of the chosen area of 100 to the integrated spectrum area. In essence, this approach is based on the assumption that the total concentration of the main blood or serum components is roughly constant.
Other transmittance, reflectance and emission techniques have been developed for measuring analytes in samples. In general, however, these methods have been found to be accurate for some, but not all, patients. To improve the accuracy, the prior art typically requires the use of complex analysis, complex equipment, or both. Thus, these methods are not well-suited for convenient, quick and simple use.
Additionally, to overcome the delay in feedback associated with sending the sample to a laboratory for analysis, the use of point of care testing has increased. Generally, this type of testing means that patient samples are tested at the bedside or within the intensive care unit of the hospital ward rather than in a centralized laboratory. Many of the present point of care methods, however, are more expensive than the conventional methods. For example, one widely-used point of care device, made by I-Stat Corporation, analyzes whole blood for sodium, potassium, chloride, CO.sub.2, urea, glucose and hematocrit. The cost of reagents for this panel of tests is about twelve dollars. In contrast, the reagent cost per analyte for a typical large central laboratory analyzer is on the order of a few cents. Thus, the benefit and practicality of current devices providing immediate feedback may be outweighed by the cost, especially given the fiscal constraints of today's hospital environment.